Hemodialysis, hemofiltration and other forms of extracorporeal blood processing are in widespread and successful use. Nevertheless, one area in which there remains a need for improvement is to allow cartridges to be used for longer periods of time without degradation of performance due to clotting and clogging. There is also need for cartridges and flow system that can minimize the need for complex anticoagulation modalities.
For an understanding of the problems, it is useful to describe some considerations that pertain generally to the extracorporeal processing of blood and to conventional hemodialysis. In general, in an extracorporeal blood flow circuit, there is provided a membrane that is semi-permeable, having a desired small pore size so as to allow some substances to pass through the membrane while other substances do not pass through the membrane, based on the respective molecular weights of the substances. Typically one side of the membrane is exposed to blood and the other side of the membrane is exposed to dialysate or filtrate. Passage of mass through the membrane can be driven by pressure difference across the membrane (convection), or by concentration differences (diffusion), or by a combination of both of these mechanisms.
Fluids and their Properties
Dialysate is an aqueous buffer solution that resembles water in its physical properties, and its fluid mechanical behavior is approximately Newtonian, and it can be used over a wide range of velocities and shear rates. The physical and chemical properties of the surfaces that are in contact with dialysate are relatively unimportant. Dialysate does not form clots. In general, dialysate is a solution that does not impose very demanding requirements on the system or the surfaces that it contacts.
Blood is a complex fluid that tends to form clots if any of various criteria are not satisfied. Clots or thrombi can be very dangerous to the patient if they travel with the blood and enter the patient's body. Also, clots can degrade the performance of the membrane or the cartridge in terms of mass exchange and flow. In general, one property of blood is that motion of blood helps to avoid the formation of clots. This implies it is undesirable for a blood flow system to have flow stagnation points or flow stagnation regions. More specifically, some of the literature characterizes the shear rate of blood flow as a suitable indicator of the tendency for blood to form clots. It is generally considered that there is a preferred shear rate for blood, which is the range of from about 300 sec−1 to about 2700 sec−1 or more depending on the level and type of anticoagulation and on the surface properties of surfaces in contact with blood. If the shear rate is either below that range or above that range, clots tend to form. A still further belief about the properties of blood is that it is undesirable for the shear rate to change drastically within a short distance along a flowpath. This criterion is referred to as shear rate gradient and is discussed elsewhere herein. Still other criteria pertain to various physical and chemical properties of the blood-facing surface that relate to non-thrombogenicity or hemocompatibility, as discussed in more detail elsewhere herein. Also, exposure of blood to air can result in clots. There are multiple physical and chemical mechanisms that can lead to formation of clots, and the mechanisms of clot formation are not always the same in regard to all of these criteria, but these criteria give general guidance about how to avoid or reduce or minimize clot formation. Also, blood is a non-Newtonian fluid, specifically a shear-thinning non-Newtonian fluid.
Overall Flow Considerations (Conventional Hemodialysis)
Referring now to FIGS. 1 and 2, FIG. 1 illustrates a conventional hemodialysis system and FIG. 2 illustrates a conventional hemodialysis cartridge or filter containing a plurality of hollow fibers that are semi-permeable. A conventional hemodialysis cartridge contains thousands of such hollow fibers arranged in parallel with each other, originating at a supply end header and terminating at a discharge end header. At each end header there is a barrier, formed by potting with a hemocompatible polymer resin, normally polyurethane or equivalent, so that the interiors of the fibers are in fluid communication with a first flow compartment and the exteriors of the fibers are in communication with a second flow compartment distinct from the first flow compartment. The fibers are flexible because they are long and narrow. In a conventional dialyzer containing many hollow fibers, the fibers are bundled inside a housing, usually a cylindrical housing. The housing also has a housing supply fluid connection and a housing discharge fluid connection.
In conventional hemodialysis, blood enters the supply end header, then the blood flows through the lumens of the fibers while undergoing mass exchange through the walls of the hollow fibers, and a roughly similar quantity of blood exits the hollow fibers into the discharge end header to be returned to the patient. This is termed the blood compartment. Dialysate enters at one end of the housing, flows past the exteriors of the fibers, and exits at the other end of the housing. This is termed the dialysate compartment. In conventional hemodialysis, blood and dialysate flow in a counterflow relationship, i.e., in opposite directions. In the housing, pressure drop occurs as dialysate flows from the housing supply end of the housing to the housing discharge end of the housing. Inside the fibers, pressure drop occurs as blood flows from the supply end of the hollow fiber to the discharge end of the hollow fiber. The absolute and relative pressures and pressure drops of the two fluid streams, and other operating parameters, can be controlled so as to result in ultrafiltration. The nature of these fluid flows and pressure drops in the system defines the type of therapy such as hemodiafiltration or hemodialysis, as described elsewhere herein.
In the design of conventional hemodialysis cartridges, some attention is given to the distribution of flow both of blood and of dialysate. The literature suggests that in the absence of appropriate design features, blood flow tends to be distributed nonuniformly among the fibers, typically being greater for fibers located closer to the center of the fiber bundle. Also, dialysate flow tends to be distributed nonuniformly, typically being greater closer to the periphery of the fiber bundle. These nonuniformities and also the nature of the mismatch of these nonuniformities can degrade the effectiveness of the dialyzer in terms of mass (solute) exchange (or clearance) between blood and dialysate. A further area of concern in this regard is that it is possible for some fibers that are near each other to clump together somewhat randomly in localized places, which results in undesirable effects known as channeling. If clumping occurs, there are likely to be some more wide-open regions or channels within the housing and some other clumped-together regions within the housing. The pattern of these regions may vary along the length of the cartridge and might also vary with time. If clumping happens, the open spaces may carry a disproportionate share of dialysate flow. This means that some other fibers or regions of the fiber bundle may carry undesirably small amounts of dialysate, and so do not perform mass exchange as well as intended. Difficulties arising from these issues include not knowing what dose of dialysis the patient actually receives.
Design approaches to reduce or avoid clumping include: the use of appropriate values of the porosity of the fiber bundle inside the housing; the use of wavy fibers; and the use of spacer fibers (which may be either solid or yarn).
Selection of an appropriate porosity or packing factor for the fibers within the housing space has some effect in lessening the tendency for clumping. The porosity fraction of the fiber bundle is the total cross-sectional area of void space between the fibers enclosed in the housing (i.e., the inter fiber space), divided by the total cross-sectional area inside the housing. The packing fraction is the total area enclosed by the external perimeters of the fibers, compared to the total area inside the housing. The relation between the porosity fraction and the packing fraction is that the total of the porosity fraction and the packing fraction is unity. For conventional hemodialysis cartridges that have straight fibers, typical values of the porosity of the fiber bundle range from 70% to 30% (corresponding to a packing fraction ranging from 30% to 70%).
In regard to waviness, the fibers are sometimes manufactured so that instead of being straight, they have a wavy pattern resembling a sinusoid having a small amplitude and a defined spatial period or wavelength. Wavy fibers, if used, typically have a spatial period or wavelength of from 0.5 cm to 2 cm and preferably about 0.8 to 1.0 cm. The wavy fibers provide a tendency toward self-spacing and discouraging of clumping. For conventional hemodialysis cartridges that have wavy fibers, typical values of fiber bundle porosity are normally somewhat less than that for straight fibers.
Another practice sometimes used is to include in the fiber bundle some spacer fibers. Spacers do not carry flow internally, but are potted in the end barriers similarly to the potting of ordinary hollow fibers. Spacers may be either solid fibers or multi-fiber yarns. If the spacers are solid fibers, they may have more rigidity than do corresponding hollow fibers.
Flow Transition at Ends of Housing (Conventional Hemodialysis)
Referring now to FIG. 2, in a conventional hemodialysis cartridge, another area of design is in regard to transition regions that involve changes of flow direction or flow area, particularly regarding flow of dialysate inside the housing flowing past the outsides of the fibers. Such changes may occur at the housing supply port and at the housing discharge port connected to the housing, because these ports generally are directed sideways with respect to the housing while the overall direction of fluid flow between fibers in the bundle is axial, along the length of the housing. As flow progresses into and through and then out of the housing, the flow typically transitions from a sideways connection and a sideways flow direction at the outside of the fiber bundle, to a flow along the axial direction of the fiber bundle where the flow is hopefully distributed as uniformly as possible across the cross-section of the housing, and then back to a sideways connection and a sideways flow direction. One design feature that is sometimes used, when flow enters and exits from the side, is an orbital distributor. An orbital distributor is a channel, having open dimensions substantially greater than the dimension between individual fibers of the fiber bundle, which is adjacent to a side port and which provides or collects fluid to or from substantially 360 degrees around the fiber bundle. Typically, an orbital distributor has an open direction that faces away from the middle of the lengthwise direction of the cartridge. In a conventional hemodialysis cartridge, if an orbital distributor is present, typically it is present at both ends (supply and discharge) of the cartridge, and is geometrically identical at both ends of the cartridge.
Another or related design feature that is sometimes used, especially in designs containing an orbital distributor, is the fanning-out of fibers in the end region, between the orbital distributor and the barrier in which the fibers are potted. Such fanning-out allows the flow to more easily travel transverse to the lengthwise direction of the fibers than would be the case if the inter-fiber spacing were maintained as it is in the main part of the housing. In conventional hemodialysis cartridges, if fanning-out is present, typically it is identical at both ends of the cartridge. If fanning-out is present, typically it is present such that the ratio of the overall cross-sectional area of the fanned fiber bundle to the overall cross-sectional area of the unfanned fiber bundle is in the range of 1.20 to 1.70. There is no known strict requirement or criterion for selection of this ratio.
Fiber Properties (Conventional Hemodialysis)
In a majority of conventional hemodialysis cartridges, the typical pore size of the smallest pores in the semi-permeable membrane is approximately 2 to 7 nanometers, which is suitable for allowing water, small molecules and middle molecules to pass through while retaining large molecules especially albumin. More specifically, the pores having this pore size are typically located at one surface of the membrane, which is a surface that is smooth compared to the opposite surface of the membrane. Such membranes commonly are referred to as asymmetric membranes. Typically for conventional hemodialysis cartridges, the surface that is smooth is the interior lumen surface of the hollow fibers (which is the surface that is contacted by the blood). The term “smooth” can be considered to mean that the rms (root-mean-square) value of the surface roughness is smaller than 100 nanometers. Typically, pores towards the outer surface of such a hollow fiber are larger than pores near the inner surface. In most conventional hemodialysis cartridges, the exterior surface of the hollow fibers (which is contacted by the dialysate) is not smooth. Typically the outside surfaces have surface roughness that is greater than 100 nanometers (root-mean-square). Much of this roughness exists in the form of craters at the surface (rather than pores that are involved in the filtration function).
By far the most common material for making the hollow fibers is a mixture of polyethersulfone (PES) and/or its polymer variants, combined with polyvinylpyrrolidone (PVP). This combination of materials is suitable to make a fiber that is smooth on one surface but not both surfaces, as a function of manufacturing process conditions. The combination of polyethersulfone and polyvinylpyrrolidone is not suitable for making so-called symmetric fibers where both internal and external surfaces of the fiber are smooth.
So-called symmetric fibers have also been made, having a smooth surface on both the inside surface and the outside surface, with both of those smooth surfaces containing the smallest pores. There may be larger pores between the two smooth surfaces. The smoothness on both surfaces generally has not been required for clinical or physiological applications or therapies. Instead, the smoothness on both surfaces has simply happened as a consequence of the manufacturing process in combination with the properties of certain particular polymeric materials. Only a few specific polymeric materials are suitable for manufacturing symmetric fibers. These materials include: polyacrilonitrile (referred to as AN69); cellulose triacetate and other cellulosics; PEPA (polyester polymer alloy, produced by Nikkiso); and polymethylmethacrylate (PMMA).
Some dialyzers use straight fibers, while others use wavy fibers, as discussed in regard to packing fraction. One way of manufacturing wavy fibers is to take hot soft extruded polymer as it leaves the extruder, and put it through a mechanical process that pushes the fiber sideways in one direction out of a straight-line path as it passes through the apparatus, and then pushes the fiber in the opposite direction out of a straight-line path, with this pushing or deforming process being repeated many times. If the resulting fiber shape is considered to be at least approximately sinusoidal, the mechanical parameters of this process can define both the amplitude and the wavelength of the undulations in the fiber.
Further Flow Considerations (Conventional Hemodialysis)
In the conventional arrangement of a hemodialyzer, if a clot forms inside a hollow fiber, the clot generally blocks all blood flow through that fiber and prevents the use of that fiber in filtration or mass exchange for the remainder of the useful life of the cartridge. Such blockage degrades the performance of the cartridge because only the remaining, unclotted fibers are able to carry any blood flow through them and thereby perform a useful function. This is illustrated in FIG. 3 and FIG. 4.
In conventional hemodialysis, the geometric transitions inside the housing near the ends of the fibers, such as orbital distributors and fanning-out of the hollow fibers, if they are present in the design of the cartridge, affect the flow of the dialysate. However, in conventional hemodialysis, the flow details of this transition are important mainly to the extent that they influence the efficiency of the mass exchange. Because of its nature and fluid properties, dialysate is a simple fluid that does not present any possibility of clotting.
In general, passage of substances through the semi-permeable membrane can be due to either diffusion, which results from differences in concentration of chemical species, or convection, which results from pressure difference. It is also possible that both of these processes can be active in the same cartridge, especially with high-flux membranes, which facilitate more connective transport during dialysis.
In conventional hemodialysis, the blood flows inside the lumen along the length of the lumen having a pressure drop from a blood inlet end of the lumen to the blood outlet end of the lumen. Dialysate flows lengthwise the length of the housing, experiencing a pressure drop from the dialysate inlet end of the housing to the dialysate outlet end of the housing. Typically the direction of blood flow is opposite the direction of the dialysate flow, so the end of the housing that has the highest blood pressure is the end of the housing that has the lowest dialysate pressure, and the end of the housing that has the lowest blood pressure is the end of the housing that has the highest dialysate pressure. There can be any desired relation between the absolute levels of those two pressure profiles, because it is possible to adjust the absolute pressure level of either or both of those profiles. This pressure adjustment is now possible with modern dialysis machines that include balancing pressure features.
One common relation is that the two pressure profiles cross each other at some point along the length of the cartridge. In such a situation, for some portion of the length of the cartridge, the direction of the transmembrane pressure difference is outward, causing convective flow from the inside of the fiber outward. In a different portion of the length of the cartridge, the direction of the transmembrane pressure difference is inward, causing convective flow from the outside of the fiber inward. In applications such as high flux hemodialysis where internal filtration is manifested, there is a location somewhere within the cartridge where the pressure of blood inside the hollow semi-permeable fiber equals the pressure of dialysate on the outside of the hollow semi-permeable fiber. In the region between this point and one end of the cartridge, the transmembrane pressure difference causes convective flow of liquid outward through the membrane. In the region between this point and the other end of the cartridge, the transmembrane pressure difference causes convective flow of liquid through the membrane in the opposite direction. Thus, there is offsetting convective flow of liquid across the membrane. This situation is designated Internal Filtration or High Flux Hemodialysis, and is favorable for increased clearance of middle molecules, because liquid that flows from the blood into the dialysate contains middle molecules, but after this liquid mixes with the dialysate and some of the dialysate flows into the blood, that liquid only contains whatever is the concentration of middle molecules is in the dialysate, which is a low concentration. This situation is favorable for clearance of middle molecules. With a higher level of internal filtration, a greater removal of middle molecules can be achieved.
A related conventional technology is ultrafiltration, which has both medical and industrial applications. Ultrafiltration refers only to the passage of substances through the membrane under the action of pressure difference. Fluid to be treated is supplied to the ultrafilter, and a portion of that fluid is discharged from the other side of the membrane as filtrate. Ultrafiltration membranes are defined by the molecular weight cut-off (MWCO) of the membrane used. Typically, for dialysis applications, the pore size in the hollow fiber membranes is approximately 0.2 nanometers to 5 nanometers. In outside-in ultrafiltration, liquid is supplied to the housing, i.e., to the outsides of the hollow fibers, and filtrate is withdrawn from the insides of the hollow fibers through a header. In applications such as water purification, this process is often performed in the dead-end mode. Typically, only one header is used for removal of filtrate, i.e., if both ends of the fibers are potted, one header is a dead-end.
The current standard of practice in extracorporeal blood therapy such as hemodialysis, when mass exchange is desired, is to cause the blood flow through the lumens of the hollow fiber and to cause the dialysate to flow past the exterior of the fibers.